1. Field of the Invention
The present invention relates generally to methods for controlling cell death when a cell is exposed to one or more potentially lethal cellular insults. More particularly, the present invention is directed to the discovery that the cellular production of reactive oxygen species plays an important role in apoptosis or necrosis of a cell when it is exposed to a potentially lethal insult. By controlling the production of reactive oxygen species, cells may be saved which would otherwise die due to the production of excessive reactive oxygen species. Alternatively, cells which resist intentional lethal insults may be rendered more susceptible to death by limiting their ability to prevent production of reactive oxygen species when they are subjected to such intentional insults.
2. Description of Related Art
The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the appended bibliography.
The phenomenon of cell death has been, and continues to be, the subject of a great deal of investigation. Many studies have been made to ascertain, identify and understand the mechanism(s) involved in cell death. Researchers have hoped that once the underlying mechanisms of cell death are understood that it will then be possible to construct procedures for controlling cell death. This would allow researchers to prevent cells from dying which otherwise would die when exposed to a potentially lethal cellular insult. Conversely, researchers could utilize their knowledge of the mechanism of cell death to hasten death of cancer cells or other undesirable cells which resist death even when subjected to a variety of cellular insults which normally would be lethal.
Some of the research regarding the mechanisms of cell death have centered around the identification and study of proteins which appear to play a role in inhibiting cell death when cells are exposed to potentially lethal insults. An example of such a protein is bcl-2. The protooncogene bcl-2 was discovered by translocation analysis of B-cell lymphomas (1). Subsequently it was reported that its protein product, bcl-2, is targeted to the inner membrane of mitochondria and that apoptosis of B cells, induced by the withdrawal of serum and growth factors, is inhibited by bcl-2 (2). The normal function of bcl-2 is unknown, as is the mechanism by which bcl-2 inhibits apoptosis. Furthermore, bcl-2 has little homology with other known proteins except the Epstein-Barr virus protein BHRF1 [for which no function is known (3)], although some homology to ras has been suggested (4).
Bcl-2 inhibits apoptosis in only a subset of hematopoietic cells. Bcl-2 has also been reported to inhibit the death of sympathetic neurons cultured in the absence of NGF (8).
There is a present and continuing need to discover and investigate the mechanism(s) which are involved in cell death. Once an understanding of a given cell death mechanism is understood, it would be desirable to be able to use this understanding to develop methods for controlling cell death. The control of cell death would not only allow one to prolong the life of desirable cells, but would also allow one to shorten the life of undesirable cells.